Pathways of sphingolipid metabolism provide a very rich network of bioactive molecules whose emerging functions suggest key roles in the regulation of cell function. In particular, published and preliminary results suggest the global hypothesis that pathways linked to ceramide formation play key roles in cytokine- and chemotherapy-induced cancer cell death whereas the sphingolipid sphingosine-l-phosphate (SIP) may emerge as a key and novel regulator of tumor neo-vascularization. This overall hypothesis will be approached through the activities of 3 distinct projects: Project 1 will address the specific hypothesis that the de novo synthesis of ceramide and sphingomyelin hydrolysis define two distinct pathways of ceramide formation which mediate synergistic tumor cell death through two distinct mechanisms. Project 2 will test the specific hypothesis that the ability to sensitize uninfected and/or resistant tumor cells (by addition of antisense molecules, chemotherapy, or agents that induce ceramide levels), would promote a more proapoptotic phenotype, and this would facilitate bystander activity and achieve greater tumor cell killing. Project 3 will test the hypothesis that sphingosine kinase and its product SIP regulate tumor angiogenesis, and inhibiting this pathway could inhibit tumor angiogenesis. These 3 projects will be supported by an Administrative Core and by a unique Lipidomics Core that will provide analytical and synthetic lipid chemistry. The results of these interactive studies would bring this last frontier of cellular biochemistry (sphingolipid metabolism) into cancer biology research, generating significant and unique insights into cancer cell death and tumor angiogenesis. The studies should also result in the identification of novel strategies for cancer therapeutics aimed at inducing cancer cell death and/or inhibition of tumor angiogenesis.